Certain-4-hydroxy-proline derivatives

ABSTRACT

Compounds of the formula ##STR1## are useful as intermediates in the preparation of various hypotensive agents.

This application is a division of Ser. No. 230,206 filed Feb. 2, 1981now U.S. Pat. No. 4,356,182 which in turn is a division of Ser. No.86,905 filed Oct. 22, 1979, now U.S. Pat. No. 4,291,040.

BACKGROUND OF THE INVENTION

Mercaptoacyl derivatives of proline and 4-hydroxyproline are disclosedas useful antihypertension agents due to their angiotensin convertingenzyme inhibition activity in U.S. Pat. No. 4,105,776 on Ondetti et al.

Mercaptoacyl derivatives of proline wherein the acyl sidechain can besubstituted by an alkyl or trifluoromethyl group and the proline can besubstituted with one or more halogens are also useful as angiotensinconverting enzyme inhibitors as note Ondetti et al. U.S. Pat. No.4,154,935.

Mercaptoacyl 3,4-dehydroprolines are disclosed as usefulantihypertension agents due to their angiotensin converting enzymeinhibition activity in U.S. Pat. No. 4,129,566 of Ondetti et al.

Mercaptoacyl derivatives of proline wherein the acyl sidechain can besubstituted with a lower alkylthio group are also disclosed asangiotensin converting enzyme inhibitors by Ondetti et al. in U.S. Pat.No. 4,116,962.

SUMMARY OF THE INVENTION

This invention relates to new mercaptoacyl 4,4-disubstituted prolines offormula I and salts thereof ##STR2## and mercaptoacyl 4-substituteddehydroproline compounds of formula II and salts thereof ##STR3##

R in both formulas represents hydrogen or lower alkyl.

R₁ in both formulas represents lower alkyl, lower alkenyl, loweralkynyl, ##STR4## --(CH₂)_(m) -cycloalkyl, α-naphthyl, β-naphthyl,##STR5##

R₂ and R₃ in both formulas are independently selected from hydrogen,lower alkyl, lower alkylthio, and halo substituted lower alkyl.

n in both formulas is zero, one or two.

R₄ is hydrogen, a hydrolyzably removable protecting group, a chemicallyremovable protecting group, or ##STR6##

R₅ is hydrogen, a hydrolyzable removable protecting group, a chemicallyremovable protecting group, or ##STR7##

m is zero, one, two or three.

R₆ is hydrogen, lower alkyl of 1 to 4 carbons, especially methyl, loweralkoxy of 1 to 4 carbons, especially methoxy, lower alkylthio of 1 to 4carbons, especially methylthio, chloro, bromo, fluoro, trifluoromethylor hydroxy. The hydroxy substituted compounds are obtained by heatingthe corresponding methoxy substituted compound with pyridine HCl.

X is oxygen or sulfur.

DETAILED DESCRIPTION OF THE INVENTION

The invention in its broadest aspects relates to the mercapto4,4-disubstituted prolines and the mercaptoacyl-4-substituteddehydroproline compounds of formulas I and II above, to compositionscontaining such compounds and to the method for using such compounds asanti-hypertensive agents. This invention is also directed to certainnovel intermediates useful in the preparation of compounds of formulas Iand II.

The term lower alkyl as used in defining the symbols R, R₁, R₂ and R₃are straight or branched chain hydrocarbon radicals having up to sevencarbons, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, isopentyl, etc. The preferred lower alkyl groups are upto four carbons with methyl and ethyl being most preferred. Similarly,the terms lower alkoxy and lower alkylthio refer to such lower alkylgroups attached to an oxygen or sulfur.

The term cycloalkyl refers to saturated rings of 3 to 7 carbon atomswith cyclohexyl being most preferred.

The term halo substituted lower alkyl refers to such lower alkyl groupsdescribed above in which one or more hydrogens have been replaced bychloro, bromo or fluoro groups such as trifluoromethyl, which ispreferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl,bromomethyl, etc.

The term lower alkenyl as used in defining the symbol R₁ aremono-unsaturated straight or branched chain hydrocarbon groups of from 2to 7 carbons such as ethenyl, propenyl, isopropenyl, butenyl, and thelike. The lower alkynyl groups are straight or branched chainhydrocarbon groups of from 2 to 7 carbons having one triple bond, e.g.,propargyl. The preferred lower alkenyl groups are from 2 to 5 carbonsand the preferred lower alkynyl groups are from 2 to 4 carbon atoms.

The term hydrolyzably removable protecting group employed in defining R₄and R₅ refers to a group that can be removed by conventional hydrolysisor ammonolysis. Acyl groups of the formula ##STR8## are suitable forthis purpose wherein R₇ can be lower alkyl of 1 to 6 carbons, loweralkyl substituted with one or more chloro, bromo or fluoro groups,--(CH₂)_(m) -cycloalkyl, an aryl group such as ##STR9## a hetero groupsuch as ##STR10## wherein m, R₆ and X are as defined above. Preferredprotecting groups are the lower alkanoyl groups having up to fourcarbons, especially acetyl, and benzoyl.

The term chemically removable protecting group employed in defining R₄and R₅ refers to groups such as p-methoxybenzyl,p-methoxybenzyloxycarbonyl, t-butoxycarbonyl, etc. These groups can beremoved without effecting the remainder of the molecule such as bytreatment with trifluoroacetic acid and anisole.

As shown in formulas I and II, the asymmetric center in the proline ordehydroproline ring is in the L-configuration. Of course, an additionalasymmetric center can be present in the mercapto sidechain dependingupon the substituents R₂ and R₃. The products of formulas I and II canaccordingly exist in stereoisomeric forms or as racemic mixturesthereof. All of these are within the scope of the invention. Thesynthesis described below can utilize the racemate or one of theenantiomers as starting materials. When the racemic starting material isused in the synthesis procedure, the stereoisomers obtained in the finalproduct can be separated by conventional chromatographic or fractionalcrystallization methods. Preferably, if there is an asymmetric center inthe mercaptoacyl sidechain, it is in the D-configuration.

Preferred compounds of formulas I and II are those wherein R ishydrogen; R₁ is lower alkyl of 1 to 4 carbons or ##STR11## wherein m iszero, one or two, and R₆ is hydrogen, methyl, methoxy methylthio,chloro, fluoro, trifluoromethyl or hydroxy; R₂ is hydrogen, methyl,trifluoromethyl, or methylthio; R₃ is hydrogen; n is zero or one; and R₄or R₅ is hydrogen. Also preferred as intermediates are the abovecompounds wherein R₄ or R₅ is acetyl or benzoyl, especially acetyl.

Most preferred are the above compounds wherein R₁ is phenyl; R₂ ishydrogen or methyl, especially methyl; R₃ is hydrogen; n is one; and R₄or R₅ is hydrogen.

The compounds of formula I are obtained by coupling the4,4-disubstituted proline of the formula ##STR12## with an acid or itschemical equivalent of the formula ##STR13## wherein R'₄ is hydrogen, R₇--CO--, or a chemically removable protecting group to yield the productof the formula ##STR14##

This reaction can be effected in the presence of a coupling agent suchas dicyclohexylcarbodiimide or the like, or the acid can be activated byformation of its mixed anhydride, symmetrical anhydride, acid halide,active ester or use of Woodward reagent, K,N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or the like. For a reviewof the methods of acylation, see Methoden der Organishchen Chemie(Houben-Weyl), Vol. XV, part II, page 1 et seq. (1974). Preferably, theacid halide, especially the acid chloride, of formula IV is reacted withthe acid of formula III.

If the proline of formula III is reacted in the ester form the resultingester product of formula V, i.e., R is alkyl, can be converted to thefree acid, i.e., R is hydrogen, by conventional means. For example, if Ris t-butyl this ester protecting group can be removed by saponification.

The product of formula V is preferably isolated and purified bycrystallization, e.g., by forming the dicyclohexylamine salt and thenconverting the salt to the free acid form by treatment with an aqueoussolution of an acid, such as potassium acid sulfate.

The product of formula V bearing the acyl group R₇ --CO-- can beconverted to the products of formula I wherein R₄ is hydrogen byconventional hydrolysis or by ammonolysis.

The products of formula I wherein R₄ is ##STR15## are obtained bydirectly oxidizing with iodine a product of formula I wherein R₄ ishydrogen.

The esters of formula I wherein R is lower alkyl can be obtained fromthe carboxylic acid compounds, i.e., wherein R is hydrogen, byconventional esterification procedures, e.g., by esterification with adiazoalkane such as diazomethane, a 1-alkyl-3-p-tolyltriazene, such as1-n-butyl-3-p-tolyltriazene, or the like.

The 4-disubstituted proline intermediate of formula III is prepared byreacting the N-protected 4-keto proline of the formula ##STR16## with asolution of the Grignard or lithium reagent

    R.sub.1 --Mg-halo or R.sub.1 --Li                          (VII)

wherein halo is Br or Cl and the N-protecting group is carbobenzyloxy orother suitable acyl protecting groups, to yield ##STR17##

The product of formula VIII will usually be obtained as a mixture ofcis- and trans-hydroxy isomers with respect to the carboxylic acid orester group.

This mixture can be separated into the individual cis-hydroxy andtrans-hydroxy isomers at this point of the synthetic procedure and theisomers can be purified by crystallization, by conversion to a salt formsuch as the 1-adamantanamine salt, or by chromatographic means.Alternatively, the mixture of cis and trans isomers can be carriedthrough to yield the compounds of formula V or formula I as a cis-transmixture. Chromatographic separation could then be performed as the laststep of the synthesis.

The N-protecting group can be removed from the intermediate of formulaVIII by hydrogenation in the presence of a palladium-carbon catalyst toyield the 4,4-disubstituted proline of formula III.

The compounds of formula II are obtained by coupling the 4-substituteddehydroproline of the formula ##STR18## with the acid or chemicalequivalent of the formula ##STR19## wherein R'₅ is hydrogen, R₇ --CO--,or a chemically removable protecting group to yield the product of theformula ##STR20##

As above, this reaction can be performed in the presence of a couplingagent such as dicyclohexylcarbodiimide or the like, or the acid can beactivated by formation of its mixed anhydride, symmetrical anhydride,acid halide, active ester or use of Woodward reagent K,N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline or the like. Preferably,the acid halide, especially the acid chloride, of formula X is reactedwith the acid of formula IX.

If the dehydroproline of formula IX is reacted in the ester form theresulting ester product of formula XI, i.e., R is alkyl, can beconverted to the free acid, i.e., R is hydrogen, by conventional means.For example, if R is t-butyl treatment with trifluoroacetic cid andanisole gives the free acid.

The product of formula XI is preferably isolated and purified bycrystallization, e.g., by forming the dicyclohexylamine salt and thenconverting the salt to the free acid form by treatment with an aqueoussolution of an acid, such as potassium acid sulfate.

The product of formula XI bearing the acyl group R₇ --CO-- can beconverted to the products of formula II wherein R₅ is hydrogen byconventional hydrolysis or by ammonolysis.

The products of formula II wherein R₅ is ##STR21## are obtained bydirectly oxidizing with iodine a product of formula II wherein R₅ ishydrogen.

The esters of formula II wherein R is lower alkyl can be obtained fromthe carboxylic acid compounds, i.e., wherein R is hydrogen, byconventional esterification procedures, e.g., by esterification with adiazoalkane such as diazomethane, a 1-alkyl-3-p-tolyltriazene, such as1-n-butyl-3-p-tolyltriazene, or the like.

The 4-substituted dehydroprolines of formula IX are obtained from theN-protected 4,4-disubstituted prolines of formula VIII. The intermediateof formula VIII is treated with a dehydrating agent such asp-toluenesulfonic acid, sulfuric acid, or potassium bisulfate to yield##STR22## The N-protecting group and ester protecting group can then beremoved by conventional procedures to yield the dehydroproline offormula IX. Alternatively, the dehydroproline of formula IX can beobtained in a single step by treating the N-protected 4,4-disubstitutedproline of formula VIII with a mixture of concentrated HCl and aceticacids and then neutralizing with ammonia.

The compounds of this invention form basic salts with a variety ofinorganic or organic bases. The salt forming ion derived from such basescan be metal ions, e.g., aluminum, alklai metal ions, such as sodium orpotassium, alkaline earth metal ions such as calcium or magnesium, or anamine salt ion, of which a number are known for this purpose, forexample, aralkylamines like, dibenzylamine, N,N-dibenzylethylenediamine,lower alkylamines like methylamine, t-butylamine, procaine, loweralkylpiperidines like N-ethylpiperidine, cycloalkylamines, likecyclohexylamine or dicyclohexylamine, 1-adamantanamine, benzathine, orsalts derived from amino acids like arginine, lysine or the like. Thephysiologically acceptable salts like the sodium or potassium salts canbe used medicinally as described below and are preferred. These andother salts which are not necessarily physiologically acceptable areuseful in isolating or purifying a product acceptable for the purposesdescribed below, as illustrated with the dicyclohexylamine salt in theexamples. The salts are produced by reacting the acid form of thecompound with an equivalent of the base supplying the desired basic ionin a medium in which the salt precipitates or in aqueous medium and thenlyophilizing. The free acid form can be obtained from the salt byconventional neutralization techniques, e.g., with potassium bisulfate,hydrochloric acid, etc.

The compounds of formulas I and II wherein R₄ and R₅ are hydrogen,##STR23## or the disulfide type substituent, especially wherein R₄ andR₅ are hydrogen, are useful as hypotensive agents. They inhibit theconversion of the decapeptide angiotensin I to angiotensin II and,therefore, are useful in relieving angiotensin related hypertension. Theaction of the enzyme renin on angiotensinogen, a pseudoglobulin in bloodplasma, produces angiotensin I. Angiotensin I is converted byangiotensin converting enzyme (ACE) to angiotensin II. The latter is anactive pressor substance which has been implicated as the causativeagent in various forms of hypertension in various mammalian species,e.g., rats and dogs. The compounds of this invention intervene in theangiotensinogen→(renin)→angiotensin I→(ACE)→angiotensin II sequence byinhibiting angiotensin converting enzyme and reducing or eliminating theformation of the pressor substance angiotensin II. Thus by theadministration of a composition containing one, or a combination ofcompounds, of formulas I and II angiotensin dependent hypertension inthe species of mammal suffering therefrom is alleviated. A single does,or preferably two to four divided daily doses, provided on a basis ofabout 0.1 to 100 mg. per kilogram of body weight per day, preferablyabout 1 to 15 mg. per kilogram of body weight per day is appropriate toreduce blood pressure. The substance is preferably administered orally,but parenteral routes such as the subcutaneous, intramuscular,intravenous or intraperitoneal routes can also be employed.

The compounds of this invention can also be formulated in combinationwith a diuretic for the treatment of hypertension. A combination productcomprising a compound of this invention and a diuretic can beadministered in an effective amount which comprises (for a 70 kg.mammal) a total daily dosage of about 30 to 600 mg., preferably about 30to 300 mg., of a compound of this invention, and about 15 to 300 mg.,preferably about 15 to 200 mg. of the diuretic, to a mammalian speciesin need thereof. Exemplary of the diuretics contemplated for use incombination with a compound of this invention are the thiazidediuretics, e.g., chlorthiazide, hydrochlorothiazide, flumethiazide,hydroglumethiazide, bendroflumethiazide, methchlothiazide,trichlormethiazide, polythiazide or benzthiazide, as well as ethacrynicacid, ticrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamterene, amiloride and spironolactone, and salts of such compounds.

The compounds of formulas I and II can be formulated for use in thereduction of blood pressure in compositions such as tablets, capsules orelixirs for oral administration or in sterile solutions or suspensionsfor parenteral administration. About 10 to 500 mg. of a compound ormixture of compounds of formula I is compounded with a physiologicallyacceptable vehicle, carrier, excipient, binder, preservative,stabilizer, flavor, etc., in a unit dosage form as called for byaccepted pharmaceutical practice. The amount of active substance inthese compositions or preparations is such that a suitable dosage in therange indicated is obtained.

Illustrative process details are set forth in the following examples forthe various reactions. These examples are preferred embodiments and alsoserve as models for the preparation of other compounds of thisinvention. The temperatures are given in degrees on the centigradescale.

EXAMPLE 1[1(S),4R]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline(a) N-Carbobenzyloxy-cis-4-hydroxy-trans-4-phenyl-L-proline

65 Ml. of 3.2M phenylmagnesium bromide in ether (0.21 mole) is added toa stirred solution of 23.8 g. (0.09 mole) ofN-carbobenzyloxy-4-keto-L-proline (prepared according to Patchett etal., J. Amer. Chem. Soc., Vol. 79, p. 189-192) in 700 ml. oftetrahydrofuran over a period of 15 minutes while the temperature ismaintained at 20°-25°. A gelatinous precipitate begins to separate after45 ml. of the Grignard solution is added. After stirring overnight, mostof the precipitate dissolves. The mixture is cooled to 15°, treated witha solution of 25 g. of ammonium chloride in 250 ml. of ice-water,stirred for one hour, and acidified with 35 ml. of 6N hydrochloric acid.The organic phase is separated and the aqueous layer is extracted twicewith 200 ml. of ethyl acetate. The organic phases are combined, dried(MgSO₄), filtered, and the solvent evaporated to give 32 g. of tanfoam-like solid. This material is treated with 200 ml. of ether-125 ml.of N sodium hydroxide, shaken in a separatory funnel and filtered toremove the gelatinous material at the interface. The aqueous phase isseparated, acidified with 22 ml. of 6N hydrochloric acid and extractedwith 100 ml. of ethyl acetate. The layers are separated and the aqueousphase is extracted twice with 50 ml. ethyl acetate. The organic phasesare combined, dried (MgSO₄), filtered and the solvent evaporated to give27.3 g. of a pale yellow foam-like residue. This material is treatedwith 150 ml. of ether to give a solution from which the productcrystallizes. After cooling overnight, the mixture is filtered to give11.8 g. of colorless solid; m.p. 120°-122°. Crystallization from 22 ml.of ethyl acetate-22 ml. of hexane yields 10.1 g. ofN-carbobenzyloxy-cis-4-hydroxy-trans-4-phenyl-L-proline; m.p. 121°-123°;[α]_(D) ²⁵ -32° (c, 1% in CHCl₃). Additional product can be obtained byconcentrating and cooling of the filtrate.

Anal: Calc'd. for C₁₉ H₁₉ NO₅ : C, 66.85; H, 5.61; N, 4.10. Found: C,66.67; H, 5.50; N, 3.99.

(b) cis-4-Hydroxy-trans-4-phenyl-L-proline

A solution of 3.0 g. (0.008 mole) ofN-carbobenzyloxy-cis-4-hydroxy-trans-4-phenyl-L-proline from part (a) in120 ml. of 2:1 methanol-water is treated with 1.0 g. of 5% palladiumcarbon catalyst and placed under 49 psi. of hydrogen. The uptake ofhydrogen is rapid (almost complete after one hour). After three hours,the catalyst is filtered through Celite, washed with methanol and thefiltrate concentrated on a rotary evaporator to yield 1.75 g. of lightgray solid cis-4-hydroxy-trans-4-phenyl-L-proline; m.p. 240°-242°;[α]_(D) ²⁵ +15° (c,1% in N HCl).

Anal: Calc'd. for C₁₁ H₁₃ NO₃.0.5 H₂ O: C, 61.10; H, 6.53; N, 6.48.Found: C, 61.06; H, 6.55; N, 6.31.

(c)[1(S),4R]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline

A stirred suspension of 4.3 g. (0.02 mole) ofcis-4-hydroxy-trans-4-phenyl-L-proline from part (b) in 50 ml. of waterand 2 g. of sodium carbonate is cooled to 5° and treated dropwise with asolution of 3.6 g. of D-3-acetylthio-2-methylpropionyl chloride in 5 ml.of ether over a period of ten minutes. An additional 2.0 g. of sodiumcarbonate is added during this period to maintain the pH at 8. Afterstirring for 90 minutes at room temperature, the solution is cooledacidified with 6N hydrochloric acid and extracted with 50 ml. of ethylacetate. The layers are separated and the aqueous phase is extractedthree times with 25 ml. of ethyl acetate. The organic phases arecombined, dried (MgSO₄), filtered, and the solvent evaporated to give7.0 g. of nearly colorless foam-like solid. This material is treatedwith 50 ml. of ethyl acetate at room temperature and then cooled to give5.35 g. of colorless [1(S),4R]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline.A small sample is crystallized from ethyl acetate; m.p. 177°-179°;[α]_(D) ²⁵ -111° (c, 1% in ethanol).

Anal. Calc'd. for C₁₇ H₂₁ NO₅ S: C, 58.10; H, 6.02; N, 3.99; S, 9.12.Found: C, 58.30; H, 5.99; N, 3.88; S, 9.21.

EXAMPLE 2[1(S),4R]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-proline

5.1 g. (0.015 mole) of[1(S),4R]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline,under argon, is treated with 10 ml. of concentrated ammonia in 25 ml. ofwater. The stirred mixture becomes a solution in several minutes and isallowed to stand for two hours at room temperature. The solution is thencooled and extracted twice with 20 ml. of ethyl acetate. The aqueousphase is layered with 20 ml. of ethyl acetate, acidified with 6Nhydrochloric acid and the layers separated. The aqueous phase isextracted twice with 20 ml. of ethyl acetate. The organic phases arecombined, dried (MgSO₄), filtered and the solvent evaporated to give 4.8g. of foam-like product. This material is dissolved in 10 ml. of ethylacetate and diluted with 10 ml. of hexane. The material initiallyseparates as an oil and then crystallizes. After cooling overnight, thecolorless solid is filtered under argon and dried to yield 4.1 g of [1(S),4R]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-proline;m.p. 152°-154°; [α]_(D) ²⁵ -57° (c, 1% in ethanol).

Anal: Calc'd. for C₁₅ H₁₉ NO₄ S.0.25 H₂ O: C, 57.48; H, 6.27; N, 4.47;S, 10.23; SH,10.02. Found: C, 57.81; H, 6.24; N, 4.41; S, 10.14;SH,9.90.

EXAMPLE 3[(S),2S]-1-[(3-Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-phenyl-L-proline

A mixture of 8.0 g. ofN-carbobenzyloxy-cis-4-hydroxy-trans-4-phenyl-L-proline from Example1(a) in 125 ml. of glacial acetic acid and 50 ml. of concentratedhydrochloric acid is stirred at room temperature (CO₂ is evolved) andthen refluxed for one hour. The resulting pale brown solution isconcentrated on a rotary evaporaton and the residual oil is dissolved in50 ml. of acetonitrile. The solvent is removed in vacuo and the granularresidue is triturated with 100 ml. of ether and filtered to give 6.0 g.of brown solid, m.p. 130°-135° (dec.). This material is suspended in 12ml. of water and neutralized with 7N ammonia-water. The mixture iscooled, filtered, and the solid is washed with cold water to give 2.1 g.of tan 3,4-dehydro-4-phenyl-L-proline; m.p. 245°-247° (dec.); [α]_(D) ²⁵-56° (c, 1% in 1N HCl).

Anal: Calc'd. for C₁₁ H₁₁ NO₂ : C, 69.82; H, 5.86; N, 7.40. Found: C,69.00; H, 5.73; N, 7.27.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid

A stirred mixture of 2.0 g. (0.01 mole) of3,4-dehydro-4-phenyl-L-proline from part (a) in 25 ml. of water and 1.5g. of sodium carbonate is cooled to 12° and treated dropwise with asolution of D-3-acetylthio-2-methylpropionyl chloride in 5 ml. of etherover a period of ten minutes. An additional 0.5 g. of sodium carbonateis added during this period to maintain the pH at 8. The ice bath isremoved and the mixture is allowed to stir for 90 minutes at roomtemperature. The solution is cooled, acidified with 6N hydrochloric acidand extracted with 25 ml. of ethyl acetate-25 ml. of chloroform. Thelayers are separated and the aqueous phase is extracted three times with25 ml. of chloroform. The organic phases are combined, dried (MgSO₄),filtered and the solvent evaporated to give 4.7 g. of a residual syrup.This syrup is dissolved in 30 ml. of ethyl acetate and treated with asolution of 2.0 g. of dicyclohexylamine in 10 ml. of ethyl acetate. Thesalt slowly crystallizes from solution. After cooling overnight, thecolorless solid is filtered and dried to give 3.3 g. of thedicyclohexylamine salt; m.p. 178°-180° (s. 180°). This material isrecrystallized from 90 ml. of acetonitrile to give 2.85 g. of colorless[1(S),2S]-1-[(3-acetylthio)2-methyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid, dicyclohexylamine salt; m.p. 182°-184° (dec.); [α]_(D) ²⁵ -138°(c, 1% in ethanol).

Anal: Calc'd. for C₁₇ H₁₉ NO₃ S.C₁₂ H₁₃ N: C, 67.67; H, 8.23; N, 5.44;S, 6.23. Found: C, 67.59; H, 8.33; N, 5.28; S, 6.09.

The above dicyclohexylamine salt is suspended in 30 ml. of ethylacetate, cooled and treated with 30 ml. of 10% potassium bisulfate. 10Ml. of chloroform are added and the mixture is shaken. The layers areseparated and the aqueous phase is extracted twice with 30 ml. of ethylacetate. The organic phases are combined, dried (MgSO₄), filtered andthe solvent evaporated to give 2.2 g. of foam-like colorless[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid.

EXAMPLE 4[1(S)]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid

2.2 g. of[1(S),2S]-1-[(3-Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid from Example 3, under argon, is treated with a cold solution of 8ml. of concentrated ammonia in 20 ml. of water. The stirred mixturebecomes a solution in several minutes and is allowed to stand for twohours at room temperature. The solution is cooled and extracted twicewith 20 ml. of ethyl acetate. The aqueous phase is layered with 20 ml.of ethyl acetate, acidified with 6N hydrochloric acid and the layersseparated. The aqueous phase is extracted twice with 20 ml. of ethylacetate. The organic phases are combined dried (MgSO₄), filtered and thesolvent evaporated to give 1.52 g. of a colorless foam-like solid; m.p.90°-95° (s. 45°). This is suspended in 25 ml. of hexane and filtered togive 1.35 g. of solid, m.p.; 90°-95° (s. 60° ). This material isdissolved in 50 ml. of ethyl acetate and extracted three times with 5ml. of water under argon to yield 1.1 g. of colorless foam-like solid[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid; m.p. 90°-95° (s. 60°); [α]_(D) ²⁵ -161° (c, 1% in ethanol).

Anal.: Calc'd. for C₁₅ H₁₇ NO₃ S 0.25 H₂ O: C, 60.89; H, 5.96; N, 4.73;SH, 11.17. Found: C, 60.80; H, 5.92; N, 4.48; SH, 10.64.

EXAMPLE 5[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-phenyl-L-proline

A stirred solution of N-carbobenzyloxy-4-keto-L-proline (13.2 g., 0.05mole) in 400 ml. of tetrahydrofuran is maintained at 20°-25° while 65ml. of 1.9N phenyl lithium in benzene-hexane (0.12 mole) is added over aperiod of ten minutes. The resulting turbid mixture is stirredovernight, at room temperature, poured onto a solution of 14 g. ofammonia chloride in 140 ml. of ice-water, and acidified with 23 ml. of6N hydrochloric acid. The organic phase is separated and the aqueousphase is extracted with 100 ml. of ethyl acetate. The organic phases arecombined, dried (MgSO₄), filtered and the solvent evaporated to give19.5 g. of a brown oil. This oil is treated with 100 ml. of ether and 70ml. of N sodium hydroxide and stirred. The aqueous phase is separatedand the ether layer is extracted twice with 100 ml. of water. Theaqueous phases are combined, cooled, acidified with 6N hydrochloricacid, and the product is extracted three times with 50 ml. of ethylacetate. The organic layers are combined, dried (MgSO₄), filtered andthe solvent evaporated to give 12.5 g. of a foam-like solid. Thismaterial is dissolved in 400 ml. of ethyl acetate and treated with asolution of 5.6 g. of 1-adamantanamine in 100 ml. of ethyl acetate togive a heavy precipitate of the salt. After standing overnight at roomtemperature, the tan solid is filtered, washed with ethyl acetate anddried in a desiccator to yield 15.7 g. of a mixture of trans and cisisomers of the 1-adamantanamine salt ofN-carbobenzyloxy-4-hydroxy-4-phenyl-L-proline; m.p. 205°-208° (red melt,s. 165°). Thin layer chromatography on silica gel using a mixture ofmethylene chloride, methanol, and acetic acid (8:1:1) shows the presenceof the trans and cis isomers.

A suspension of 15 g. of the above 1-adamantanamine salt in 50 ml. ofwater and 10 ml. of ethyl acetate is stirred and acidified with 7 ml. of6N hydrochloric acid. The mixture is shaken and the layers areseparated. The aqueous phase is extracted twice with 50 ml. of ethylacetate. The organic phases are combined, extracted three times with 10ml. of water, dried (MgSO₄), filtered, and the solvent evaporated togive 10.3 g. of foam-like solidN-carbobenzyloxy-4-hydroxy-4-phenyl-L-proline.

(b) 4-Hydroxy-4-phenyl-L-proline

A solution of the N-carbobenzyloxy-4-hydroxy-4-phenyl-L-proline frompart (a) is treated with a 5% palladium carbon catalyst and hydrogenatedaccording to the procedure of Example 1(b) to yield4-hydroxy-4-phenyl-L-proline.

(c)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline

The 4-hydroxy-4-phenyl-L-proline from part (b) is treated withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxo-propyl]-4-hydroxy-4-phenyl-L-proline.

EXAMPLE 6[1(S)-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-proline

The[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxo-propyl]-4-hydroxy-4-phenyl-L-prolinefrom Example 5 is treated with concentrated ammonia according to theprocedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-proline.

EXAMPLE 7[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-methyl-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-methyl-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of methyl magnesium bromide for the phenylmagnesium bromide oneobtains N-carbobenzyloxy-4-hydroxy-4-methyl-L-proline.

(b)[1(S)]-1-[3-Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-methyl-L-proline

The N-carbobenzyloxy-4-hydroxy-4-methyl-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-methyl-L-proline. This amino acid is then reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-methyl-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-methyl-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-methyl-L-proline.

EXAMPLE 8[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-methyl-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-methyl-L-proline

The N-carbobenzyloxy-4-hydroxy-4-methyl-L-proline from Example 7(a) istreated with hydrochloric acid according to the procedure of Example3(a) to yield 3,4-dehydro-4-methyl-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-methyl-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-methyl-L-proline from part (a) is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-methyl-1H-pyrrole-2-carboxylicacid.

(c) [1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-methyl-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-methyl-1H-pyrrole-2-carboxylicacid.

EXAMPLE 9 4-Ethyl-4-hydroxy-1-(3-mercapto-1-oxopropyl)-L-proline (a)N-Carbobenzyloxy-4-ethyl-4-hydroxy L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of ethylmagnesium bromide for the phenylmagnesium bromide oneobtains N-carbobenzyloxy-4-ethyl-4-hydroxy-L-proline.

(b) 1-[3-(Acetylthio)-1-oxopropyl]-4-ethyl-4-hydroxy-L-proline

The N-carbobenzyloxy-4-ethyl-4-hydroxy-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-ethyl-4-hydroxy-L-proline. This amino acid is then reacted with3-acetylthiopropionyl chloride according to the procedure of Example1(c) to yield1-[3-(acetylthio)-1-oxopropyl]-4-ethyl-4-hydroxy-L-proline.

(c) 4-Ethyl-4-hydroxy-1-(3-mercapto-1-oxopropyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield4-ethyl-4-hydroxy-1-(3-mercapto-1-oxopropyl)-L-proline.

EXAMPLE 10(2S)-2,5-Dihydro-4-ethyl-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-ethyl-L-proline

The N-carbobenzyloxy-4-ethyl-4-hydroxy-L-proline from Example 9(a) istreated with hydrochloric acid according to the procedure of Example3(a) to yield 3,4-dehydro-4-ethyl-L-proline.

(b)(2S)-1-[3-(Acetylthio)-1-oxopropyl]-2,5-dihydro-4-ethyl-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-ethyl-L-proline from part (a) is reacted with3-acetylthiopropionyl chloride according to the procedure of Example3(b) to yield(2S)-1-[3-(acetylthio)-1-oxopropyl]-2,5-dihydro-4-ethyl-1H-pyrrole-2-carboxylicacid.

(c)(2S)-2,5-Dihydro-4-ethyl-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield(2S)-2,5-dihydro-4-ethyl-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 11[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-t-butyl-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-t-butyl-L-proline

Following the procedure of Example 5(a) but substituting an equivalentamount of t-butyl lithium for the phenyllithium one obtainsN-carbobenzyloxy-4-hydroxy-4-t-butyl-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-t-butyl-L-proline

The N-carbobenzyloxy-4-hydroxy-4-t-butyl-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-t-butyl-L-proline. This amino acid is then reacted withD-3-acethylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-t-butyl-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-t-butyl-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-t-butyl-L-proline.

EXAMPLE 12[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-t-butyl-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-t-butyl-L-proline

The N-carbobenzyloxy-4-hydroxy-4-t-butyl-L-proline from Example 11(a) istreated with hydrochloric acid according to the procedure of Example3(a) to yield 3,4-dehydro-4-t-butyl-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-t-butyl-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-t-butyl-L-proline from part (a) is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-t-butyl-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-t-butyl-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-t-butyl-1H-pyrrole-2-carboxylicacid.

EXAMPLE 134-Hydroxy-4-[(4-methyl)phenyl]-1-(4-mercapto-1-oxobutyl)-L-proline (a)N-Carbobenzyloxy-4-hydroxy-4-[(4-methyl)phenyl]-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of 4-methylphenyl magnesium bromide for the phenylmagnesiumbromide one obtainsN-carbobenzyloxy-4-hydroxy-4-[(4-methyl)phenyl]-L-proline.

(b)1-[4-(Acetylthio)-1-oxobutyl]-4-hydroxy-4-[(4-methyl)phenyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(4-methyl)phenyl]-L-proline form part(a) is hydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-[(4-methyl)phenyl]-L-proline. This amino acid is thenreacted with 4-acetylthiobutyroyl chloride according to the procedure ofExample 1(c) to yield1-[4-(acetylthio)-1-oxobutyl]-4-hydroxy-4-[(4-methyl)phenyl]-L-proline.

(c) 4-Hydroxy-4-[(4-methyl)phenyl]-1-(4-mercapto-1-oxobutyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield4-hydroxy-4-[(4-methyl)phenyl]-1-(4-mercapto-1-oxobutyl)-L-proline.

EXAMPLE 14(2S)-2,5-Dihydro-4-[(4-methyl)phenyl]-1-(4-mercapto-1-oxobutyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-[(4-methyl)phenyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(4-methyl)phenyl]-L-proline fromExample 13(a) is treated with hydrochloric acid according to theprocedure of Example 3(a) to yield3,4-dehydro-4-[(4-methyl)phenyl]-L-proline.

(b)(2S)-1-[4-(Acetylthio)-1-oxobutyl]-2,5-dihydro-4-[(4-methyl)phenyl]-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-[(4-methyl)phenyl]-L-proline from part (a) is reactedwith 4-acetylthiobutyroyl chloride according to the procedure of Example3(b) to yield(2S)-1-[4-(acetylthio)-1-oxobutyl]-2,5-dihydro-4-[(4-methyl)phenyl]-1H-pyrrole-2-carboxylicacid.

(c)(2S)-2,5-Dihydro-4-[(4-methyl)phenyl]-1-(4-mercapto-1-oxobutyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield(2S)-2,5-dihydro-4-[(4-methyl)phenyl]-1-(4-mercapto-1-oxobutyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 154-Hydroxy-1-(2-mercapto-1-oxoethyl)-4-(phenylmethyl)-L-proline (a)N-Carbobenzyloxy-4-hydroxy-4-(phenylmethyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of benzylmagnesium chloride for the phenylmagnesium bromide oneobtains N-carbobenzyloxy-4-hydroxy-4-(phenylmethyl)-L-proline.

(b) 1-[2-(Acetylthio)-1-oxoethyl]-4-hydroxy-4-(phenylmethyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(phenylmethyl)-L-proline from part (a)is hydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-(phenylmethyl)-L-proline. This amino acid is then reactedwith 2-acetylthioacetyl chloride according to the procedure of Example1(c) to yield1-[2-(acetylthio)-1-oxoethyl]-4-hydroxy-4-(phenylmethyl)-L-proline.

(c) 4-Hydroxy-1-(2-mercapto-1-oxoethyl)-4-(phenylmethyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield4-hydroxy-1-(2-mercapto-1-oxoethyl)-4-(phenylmethyl)-L-proline.

EXAMPLE 16(2S)-2,5-Dihydro-1-(2-mercapto-1-oxoethyl)-4-(phenylmethyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(phenylmethyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(phenylmethyl)-L-proline from Example15(a) is treated with hydrochloric acid according to the procedure ofExample 3(a) to yield 3,4-dehydro-4-(phenylmethyl)-L-proline.

(b)(2S)-1-[2-(Acetylthio)-1-oxoethyl]-2,5-dihydro-4-(phenylmethyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(phenylmethyl)-L-proline from part (a) is reacted with2-acetylthioacetyl chloride according to the procedure of Example 3(b)to yield(2S)-1-[2-(acetylthio)-1-oxoethyl]-2,5-dihydro-4-(phenylmethyl)-1H-pyrrole-2-carboxylicacid.

(c)(2S)-2,5-Dihydro-1-(2-mercapto-1-oxoethyl)-4-(phenylmethyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield(2S)-2,5-dihydro-1-(2-mercapto-1-oxoethyl)-4-(phenylmethyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 17[1(S),4R]-1-[3-[[(4-Methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline(a) 3-[[(4-Methoxy)phenylmethyl]thio]-2-trifluoromethylpropionylchloride

A neat mixture of 1-trifluoromethylacrylic acid (3.9 g.) and4-methoxybenzylthiol (4.3 g.) is stirred at 100°-110° for one hour. Themixture is allowed to cool to room temperature and the solid isrecrystallized from cyclohexane to yield3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropanoic acid; m.p.72°-74°.

Treatment of this acid with thionyl chloride yields3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropionyl chloride.

(b)[1(S),4R]-1-[3-[[(4-Methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline

The 3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropionylchloride from part (a) is reacted withcis-4-hydroxy-trans-4-phenyl-L-proline from Example 1(b) to yield[1(S),4R]-1-[3-[[(4methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline.

EXAMPLE 18[1(S),4R]-4-Hydroxy-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-phenyl-L-proline

The[1(S),4R]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-prolinefrom Example 17 is mixed with trifluoroacetic acid and anisole undernitrogen. The solvents are removed under vacuum to yield as a residue[1(S),4R]-4-hydroxy-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-phenyl-L-proline.

EXAMPLE 19[1(S),2S]-1-[3-[[(4-Methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid

The 3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropionylchloride from Example 17(a) is reacted with3,4-dehydro-4-phenyl-L-proline from Example 3(a) to yield[1(S),2S]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid.

EXAMPLE 20[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid

The[1(S),2S]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid from Example 19 is mixed with trifluoroacetic acid and anisole andstirred under nitrogen. The solvents are removed under vacuum to yieldas a residue[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid.

EXAMPLE 21[1(S),4R]-1-[3-[[4-Methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline(a) 3-[[(4-Methoxy)phenylmethyl]thio]-2-methylthiopropionyl chloride

3-[[(4-Methoxy)phenylmethyl]thio]-2-methylthiopropanoic acid preparedaccording to the procedure of Example 10 in U.S. Pat. No. 4,116,962 istreated with thionyl chloride to yield3-[[(4-methoxy)phenylmethyl]thio]-2-methylthiopropionyl chloride.

(b)[1(S),4R]-1-[3-[[(4-Methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline

The 3-[[(4-methoxy)phenylmethyl]thio]-2-methylthiopropionyl chloridefrom part (a) is reacted with cis-4-hydroxy-trans-4-phenyl-L-prolinefrom Example 1(b) to yield[1(S),4R]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline.

EXAMPLE 22[1(S),4R]-4-Hydroxy-1-(3-mercapto-2-methylthio-1-oxopropyl)-4-phenyl-L-proline

The[1(S),4R]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-4-hydroxy-4-phenyl-L-prolinefrom Example 21 is mixed with trifluoroacetic acid and anisole undernitrogen. The solvents are removed under vacuum to yield as a residue[1(S),4R]-4-hydroxy-1-(3-mercapto-2-methylthio-1-oxopropyl)-4-phenyl-L-proline.

EXAMPLE 23[1(S),2S]-1-[3-[[(4-Methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid

The 3-[[(4-methoxy)phenylmethyl]thio]-2-methylthiopropionyl chloridefrom Example 21(a) is reacted with 3,4-dehydro-4-phenyl-L-proline fromExample 3(a) to yield[1(S),2S]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid.

EXAMPLE 24[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methylthio-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid

The[1(S),2S]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-methylthio-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid from Example 23 is mixed with trifluoroacetic acid and anisole andstirred under nitrogen. The solvents are removed under vacuum to yieldas a residue[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methylthio-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid.

EXAMPLE 25[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(3-fluorophenyl)-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-(3-fluorophenyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of 3-fluorophenylmagnesium bromide for the phenylmagnesiumbromide one obtainsN-carbobenzyloxy-4-hydroxy-4-(3-fluorophenyl)-L-proline.

(b)[1(S)]-1-[3-Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(3-fluorophenyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(3-fluorophenyl)-L-proline from part(a) is hydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-(3-fluorophenyl)-L-proline. This amino acid is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(3-fluorophenyl)-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(3-fluorophenyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(3-fluorophenyl)-L-proline.

EXAMPLE 26[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(3-fluorophenyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(3-fluorophenyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(3-fluorophenyl)-L-proline from Example25(a) is treated with hydrochloric acid according to the procedure ofExample 3(a) to yield 3,4-dehydro-4-(3-fluorophenyl)-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(3-fluorophenyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(3-fluorophenyl)-L-proline from part (a) is reactedwith D-3-acetylthio-2-methylpropionyl chloride according to theprocedure of Example 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(3-fluorophenyl)-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(3-fluorophenyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(3-fluorophenyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 27[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(4-chlorophenylethyl)-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-(4-chlorophenylethyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of 4-chlorophenylethyl magnesium bromide for the phenylmagnesiumbromide one obtainsN-cabobenzyloxy-4-hydroxy-4-(4-chlorophenylethyl)-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(4-chlorophenylethyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(4-chlorophenylethyl)-L-proline frompart (a) is hydrogenated according to the procedure of Example 1(b) toyield 4-hydroxy-4-(4-chlorophenylethyl)-L-proline. This amino acid isreacted with D-3-acetylthio-2-methylpropionyl chloride according to theprocedure of Example 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(4-chlorophenylethyl)-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(4-chlorophenylethyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(4-chlorophenylethyl)-L-proline.

EXAMPLE 28[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(4-chlorophenylethyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(4-chlorophenylethyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(4-chlorophenylethyl)-L-proline fromExample 27(a) is treated with hydrochloric acid according to theprocedure of Example 3(a) to yield3,4-dehydro-4-(4-chlorophenylethyl)-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(4-chlorophenylethyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(4-chlorophenylethyl)-L-proline from part (a) isreacted with D-3-acetylthio-2-methylpropionyl chloride according to theprocedure of Example 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(4-chlorophenylethyl)-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(4-chlorophenylethyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(4-chlorophenylethyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 294-Hydroxy-1-(3-mercapto-1-oxopropyl)-4-[(4-trifluoromethyl)phenyl]-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-[(4-trifluoromethyl)phenyl]-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of [(4-trifluoromethyl)phenyl]magnesium bromide for thephenylmagnesium bromide one obtainsN-carbobenzyloxy-4-hydroxy-4-[(4-trifluoromethyl)phenyl]-L-proline.

(b)1-[(3-Acetylthio)-1-oxopropyl]-4-hydroxy-4-[(4-trifluoromethyl)phenyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(4-trifluoromethyl)phenyl]-L-prolinefrom part (a) is hydrogenated according to the procedure of Example 1(b)to yield 4-hydroxy-4-[(4-trifluoromethyl)phenyl]-L-proline. This aminoacid is reacted with 3-acetylthiopropionyl chloride according to theprocedure of Example 1(c) to yield1-[3-(acetylthio)-1-oxopropyl]-4-hydroxy-4-[(4-trifluoromethyl)phenyl]-L-proline.

(c)4-Hydroxy-1-(3-mercapto-1-oxopropyl)-4-[(4-trifluoromethyl)phenyl]-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield4-hydroxy-1-(3-mercapto-1-oxopropyl)-4-[(4-trifluoromethyl)phenyl]-L-proline.

EXAMPLE 30(2S)-2,5-Dihydro-1-(3-mercapto-1-oxopropyl)-4-[(4-trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-[(4-trifluoromethyl)phenyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(4-trifluoromethyl)phenyl]-L-prolinefrom Example 29(a) is treated with hydrochloric acid according to theprocedure of Example 3(a) to yield3,4-dehydro-4-[(4-trifluoromethyl)phenyl]-L-proline.

(b)(2S)-1-[3-(Acetylthio)-1-oxopropyl]-2,5-dihydro-4-[(4-trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylicacid

The 3,4-dihydro-4-[(4-trifluoromethyl)phenyl]-L-proline from part (a) isreacted with 3-acetylthiopropionyl chloride according to the procedureof Example 3(b) to yield(2S)-1-[3-(acetylthio)-1-oxopropyl]-2,5-dihydro-4-[(4-trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylicacid.

(c)(2S)-2,5-Dihydro-1-(3-mercapto-1-oxopropyl)-4-[(4-trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield(2S)-2,5-dihydro-1-(3-mercapto-1-oxopropyl)-4-[(4-trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylicacid.

EXAMPLE 31[1(S)]-4-Hydroxy-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(2-methoxyphenyl)-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-(2-methoxyphenyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of (2-methoxyphenyl)magnesium bromide for the phenylmagnesiumbromide one obtainsN-carbobenzyloxy-4-hydroxy-4-(2-methoxyphenyl)-L-proline.

(b)[1(S)]-1-[3-[[(4-Methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-hydroxy-4-(2-methoxyphenyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(2-methoxyphenyl)-L-proline from part(a) is hydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-(2-methoxyphenyl)-L-proline. This amino acid is reacted with3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropionyl chloridefrom Example 17(a) to yield[1(S)]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-hydroxy-4-(2-methoxyphenyl)-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(2-methoxyphenyl)-L-proline

The product from part (b) is treated with trifluoroacetic acid andanisole according to the procedure of Example 18 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(2-methoxyphenyl)-L-proline.

EXAMPLE 32[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(2-hydroxyphenyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(2-methoxyphenyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(2-methoxyphenyl)-L-proline fromExample 31(a) is treated with hydrochloric acid according to theprocedure of Example 3(a) to yield3,4-dehydro-4-(2-methoxyphenyl)-L-proline.

(b)[1(S),2S]-1-[3-[[(4-Methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-2,5-dihydro-4-(2-methoxyphenyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(2-methoxyphenyl)-L-proline from part (a) is reactedwith 3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropionylchloride from Example 17(a) to yield[1(S),2S]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-2,5-dihydro-4-(2-methoxyphenyl)-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(2-hydroxyphenyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with trifluoroacetic acid andanisole according to the procedure of Example 20 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(2-methoxyphenyl)-1H-pyrrole-2-carboxylicacid. The latter is treated with pyridine hydrochloride for one hour at100° to give[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(2-hydroxyphenyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 33[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-methylthio)phenylmethyl]-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-[(4-methylthio)phenylmethyl]-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of 4-methylthiobenzyl magnesium bromide for the phenylmagnesiumbromide one obtainsN-carbobenzyloxy-4-hydroxy-4-[(4-methylthio)phenylmethyl]-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-[(4-methylthio)phenylmethyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(4-methylthio)phenylmethyl]-L-prolinefrom part (a) is hydrogenated according to the procedure of Example 1(b)to yield 4-hydroxy-4-[(4-methylthio)phenylmethyl]-L-proline. This aminoacid is reacted with D-3-acetylthio-2-methylpropionyl chloride accordingto the procedure of Example 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-[(4-methylthio)phenylmethyl]-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-methylthio)phenylmethyl]-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-methylthio)phenylmethyl]-L-proline.

EXAMPLE 34[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-methylthio)phenylmethyl]-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-[(4-methylthio)phenylmethyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(4-methylthio)phenylmethyl]-L-prolinefrom Example 33(a) is treated with hydrochloric acid according to theprocedure of Example 3(a) to yield3,4-dehydro-4-[(4-methylthio)phenylmethyl]-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-[(4-methylthio)phenylmethyl]-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-[(4-methylthio)phenylmethyl]-L-proline from part (a)is reacted with D-3-acetylthio-2-methylpropionyl chloride according tothe procedure of Example 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-[(4-methylthio)phenylmethyl]-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl-4-[(4-methylthio)phenylmethyl]-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-methylthio)phenylmethyl]-1H-pyrrole-2-carboxylicacid.

EXAMPLE 35[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(2-thienyl)-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-(2-thienyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of (2-thienyl)magnesium bromide for the phenylmagnesium bromideone obtains N-carbobenzyloxy-4-hydroxy 4-(2-thienyl)-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(2-thienyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(2-thienyl)-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yieldtrans-4-hydroxy-4-(2-thienyl)-L-proline. This amino acid is reacted withD-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(2-thienyl)-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(2-thienyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(2-thienyl)-L-proline.

EXAMPLE 36[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(2-thienyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(2-thienyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(2-thienyl)-L-proline from Example35(a) is treated with hydrochloric acid according to the procedure ofExample 3(a) to yield 3,4-dehydro-4-(2-thienyl)-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(2-thienyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(2-thienyl)-L-proline from part (a) is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(2-thienyl)-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(2-thienyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(2-thienyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 374-Hydroxy-1-(3-Mercapto-1-oxopropyl)-4-[(2-thienyl)methyl]-L-proline (a)N-Carbobenzyloxy-4-hydroxy-4-[(2-thienyl)methyl]-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of [(2-thienyl)methyl]magnesium bromide for the phenylmagnesiumbromide one obtainsN-carbobenzyloxy-4-hydroxy-4-[(2-thienyl)methyl]-L-proline.

(b)1-[3-(Acetylthio)-1-oxopropyl]-4-hydroxy-4-[(2-thienyl)methyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(2-thienyl)methyl]-L-proline from part(a) is hydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-[(2-thienyl)methyl]-L-proline. This amino acid is thenreacted with 3-acetylthiopropionyl chloride according to the procedureof Example 1(c) to yield1-[3-(acetylthio)-1-oxopropyl]-4-hydroxy-4-[(2-thienyl)methyl]-L-proline.

(c) 4-Hydroxy-1-(3-mercapto-1-oxopropyl)-4-[(2-thienyl)methyl]-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield4-hydroxy-1-(3-mercapto-1-oxopropyl)-4-[(2-thienyl)methyl]-L-proline.

EXAMPLE 38(2S)-2,5-Dihydro-1-(3-mercapto-1-oxopropyl)-4-[(2-thienyl)methyl]-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-[(2-thienyl)methyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(2-thienyl)methyl]-L-proline fromExample 37(a) is treated with hydrochloric acid according to theprocedure of Example 3(a) to yield3,4-dehydro-4-[(2-thienyl)methyl]-L-proline.

(b)(2S)-1-[3-(Acetylthio)-1-oxopropyl]-2,5-dihydro-4-[(2-thienyl)methyl]-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-[(2-thienyl)methyl]-L-proline from part (a) is reactedwith 3-acetylthiopropionyl chloride according to the procedure ofExample 3(b) to yield(2S)-1-[3-(acetylthio)-1-oxopropyl]-2,5-dihydro-4-[(2-thienyl)methyl]-L-pyrrole-2-carboxylicacid.

(c)(2S)-2,5-Dihydro-1-(3-mercapto-1-oxopropyl)-4-[(2-thienyl)methyl]-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield(2S)-2,5-dihydro-1-(3-mercapto-1-oxopropyl)-4-[(2-thienyl)methyl]-1H-pyrrole-2-carboxylicacid.

EXAMPLE 39[1(S)]-4-Hydroxy-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(3-thienyl)-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-(3-thienyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of (3-thienyl)magnesium bromide for the phenylmagnesium bromideone obtains N-carbobenzyloxy-4-hydroxy-4-(3-thienyl)-L-proline.

(b)[1(S)]-1-[3-[[(4-Methoxy)-phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-hydroxy-4-(3-thienyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(3-thienyl)-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-(3-thienyl)-L-proline. This amino acid is reacted with3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropionyl chloridefrom Example 17(a) to yield[1(S)]-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-hydroxy-4-(3-thienyl)-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(3-thienyl)-L-proline

The product from part (b) is treated with trifluoroacetic acid andanisole according to the procedure of Example 18 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(3-thienyl)-L-proline.

EXAMPLE 40[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(3-thienyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(3-thienyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(3-thienyl)-L-proline from Example39(a) is treated with hydrochloric acid according to the procedure ofExample 3(a) to yield 3,4-dehydro-4-(3-thienyl)-L-proline.

(b)[1(S),2S]-2,5-Dihydro-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-(3-thienyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(3-thienyl)-L-proline from part (a) is reacted with3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethylpropionyl chloridefrom Example 17(a) to yield[1(S),2S]-2,5-dihydro-1-[3-[[(4-methoxy)phenylmethyl]thio]-2-trifluoromethyl-1-oxopropyl]-4-(3-thienyl)-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(3-thienyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with trifluoroacetic acid andanisole according to the procedure of Example 20 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-trifluoromethyl-1-oxopropyl)-4-(3-thienyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 41[1(S)]-4-(2-Furyl)-4-hydroxy-1-(3-mercapto-2-ethyl-1-oxopropyl)-L-proline(a) N-Carbobenzyloxy-4-(2-furyl)-4-hydroxy-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of (2-furyl) magnesium bromide for the phenylmagnesium bromideone obtains N-carbobenzyloxy-4-(2-furyl)-4-hydroxy-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-ethyl-1-oxopropyl]-4-(2-furyl)-4-hydroxy-L-proline

The N-carbobenzyloxy-4-(2-furyl)-4-hydroxy-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-(2-furyl)-4-hydroxy-L-proline. This amino acid is reacted withD-3-acetylthio-2-ethylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-(3-acetylthio)-2-ethyl-1-oxopropyl]-4-(2-furyl)-4-hydroxy-L-proline.

(c)[1(S)]-4-(2-Furyl)-4-hydroxy-1-(3-mercapto-2-ethyl-1-oxopropyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-(2-furyl)-4-hydroxy-1-(3-mercapto-2-ethyl-1-oxopropyl)-L-proline.

EXAMPLE 42[1(S),2S]-2,5-Dihydro-4-(2-furyl)-1-(3-mercapto-2-ethyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(2-furyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(2-furyl)-L-proline from Example 41(a)is treated with hydrochloric acid according to the procedure of Example3(a) to yield 3,4-dehydro-4-(2-furyl)-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-ethyl-1-oxopropyl]-2,5-dihydro-4-(2-furyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(2-furyl)-L-proline from part (a) is reacted withD-3-acetylthio-2-ethylpropionyl chloride to yield[1(S),2S]-1-[3-(acetylthio)-2-ethyl-1-oxopropyl]-4-(2-furyl)-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-4-(2-furyl)-1-(3-mercapto-2-ethyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-4-(2-furyl)-1-(3-mercapto-2-ethyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 434-[(2-Furyl)methyl]-4-Hydroxy-1-(2-mercapto-1-oxoethyl)-L-proline (a)N-Carbobenzyloxy-4-[(2-furyl)methyl]-4-hydroxy-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of [(2-furyl)methyl]magnesium bromide for the phenylmagnesiumbromide one obtainsN-carbobenzyloxy-4-[(2-furyl)methyl]-4-hydroxy-L-proline.

(b)1-[2-(Acetylthio)-1-oxoethyl]-4-[(2-furyl)methyl]-4-hydroxy-L-proline

The N-carbobenzyloxy-4-[(2-furyl)methyl]-4-hydroxy-L-proline from part(a) is hydrogenated according to the procedure of Example 1(b) to yield4-[(2-furyl)methyl]-4-hydroxy-L-proline. This amino acid is reacted with2-acetylthioacetyl chloride according to the procedure of Example 1(c)to yield1-[2-(acetylthio)-1-oxoethyl]-4-[(2-furyl)methyl]-4-hydroxy-L-proline.

(c) 4-[(2-Furyl)methyl]-4-hydroxy-1-(2-mercapto-1-oxoethyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield4-[(2-furyl)methyl]-4-hydroxy-1-(2-mercapto-1-oxoethyl)-L-proline.

EXAMPLE 44(2S)-4-[(2-Furyl)methyl]-2,5-dihydro-1-(2-mercapto-1-oxoethyl)-1H-pyrrole-2-carboxylicacid (a) 4-[(2-Furyl)methyl]-3,4-dehydro-L-proline

The N-carbobenzyloxy-4-[(2-furyl)methyl]-4-hydroxy-L-proline fromExample 43(a) is treated with hydrochloric acid according to theprocedure of Example 3(a) to yield4-[(2-furyl)methyl]-3,4-dehydro-L-proline.

(b)(2S)-1-[2-(Acetylthio)-1-oxoethyl]-[(2-furyl)methyl]-2,5-dihydro-1H-pyrrole-2-carboxylicacid

4-[(2-Furyl)methyl]-3,4-dehydro-L-proline from part (a) is reacted with2-acetylthioacetyl chloride according to the procedure of Example 3(b)to yield(2S)-1-[2-(acetylthio)-1-oxoethyl]-4-[(2-furyl)methyl]-2,5-dihydro-1H-pyrrole-2-carboxylicacid.

(c)(2S)-4-[(2-Furyl)methyl]-2,5-dihydro-1-(2-mercapto-1-oxoethyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield(2S)-4-[(2-furyl)methyl]-2,5-dihydro-1-(2-mercapto-1-oxoethyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 45[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-pyridyl)methyl]-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-[(4-pyridyl)methyl]-L-proline

Following the procedure of Example 5(a) but substituting an equivalentamount of [(4-pyridyl)methyl]lithium for the phenyllithium one obtainsN-carbobenzyloxy-4-hydroxy-4-[(4-pyridyl)methyl]-L-proline.

(b)[1(S)]-1-[3-(Acetyloxy)-2-methyl-1-oxopropyl]-4-hydroxy-4-(4-[(4-pyridyl)methyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(4-pyridyl)methyl]-L-proline from part(a) is hydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-[(4-pyridyl)methyl]-L-proline. This amino acid is reactedwith D-3-acetylthio-2-methylpropionyl chloride according to theprocedure of Example 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-[(4-pyridyl)methyl]-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-pyridyl)methyl]-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-pyridyl)methyl]-L-proline.

EXAMPLE 46[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-pyridyl)methyl]-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-[(4-pyridyl)methyl]-L-proline

The N-carbobenzyloxy-4-hydroxy-4-[(4-pyridyl)methyl]-L-proline fromExample 45(a) is treated with hydrochloric acid according to theprocedure of Example 3(a) to yield3,4-dehydro-4-[(4-pyridyl)methyl]-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-[(4-pyridyl)methyl]-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-[(4-pyridyl)methyl]-L-proline from part (a) is reactedwith D-3-acetylthio-2-methylpropionyl chloride according to theprocedure of Example 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-[(4-pyridyl)methyl]-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-pyridyl)methyl]-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-[(4-pyridyl)methyl]-1H-pyrrole-2-carboxylicacid.

EXAMPLE 47[1(S)]-4-Hydroxy-1-(3-mercapto-3-methyl-1-oxopropyl)-4-(3-pyridyl)-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-(3-pyridyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of (3-pyridyl) magnesium bromide for the phenylmagnesium bromideone obtains N-carbobenzyloxy-4-hydroxy-4-(3-pyridyl)-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-3-methyl-1-oxopropyl]-4-hydroxy-4-(3-pyridyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(3-pyridyl)-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-(3-pyridyl)-L-proline. This amino acid is reacted withD-3-acetylthio-3-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-3-methyl-1-oxopropyl]-4-hydroxy-4-(3-pyridyl)-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-3-methyl-1-oxopropyl)-4-(3-pyridyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-3-methyl-1-oxopropyl)-4-(3-pyridyl)-L-proline.

EXAMPLE 48[1(S),2S]-2,5-Dihydro-1-(3-mercapto-3-methyl-1-oxopropyl)-4-(3-pyridyl)-1H-pyrrole-2-carboyxlicacid (a) 3,4-Dehydro-4-(3-pyridyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(3-pyridyl)-L-proline from Example47(a) is treated with hydrochloric acid according to the procedure ofExample 3(a) to yield 3,4-dehydro-4-(3-pyridyl)-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-3-methyl-1-oxopropyl]-2,5-dihydro-4-(3-pyridyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(3-pyridyl)-L-proline from part (a) is reacted withD-3-acetylthio-3-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-3-methyl-1-oxopropyl]-2,5-dihydro-4-(3-pyridyl)-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-3-methyl-1-oxopropyl)-4-(3-pyridyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-3-methyl-1-oxopropyl)-4-(3-pyridyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 49[1(S)]-4-Ethenyl-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline(a) N-Carbobenzyloxy-4-ethenyl-4-hydroxy-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of ethenylmagnesium bromide for the phenylmagnesium bromide oneobtains N-carbobenzyloxy-4-ethenyl-4-hydroxy-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-ethenyl-4-hydroxy-L-proline

The N-carbobenzyloxy-4-ethenyl-4-hydroxy-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-ethenyl-4-hydroxy-L-proline. This amino acid is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-ethenyl-4-hydroxy-L-proline.

(c)[1(S)]-4-Ethenyl-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-ethenyl-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline.

EXAMPLE 50[1(S),2S]-2,5-Dihydro-4-ethenyl-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-ethenyl-L-proline

The N-carbobenzyloxy-4-ethenyl-4-hydroxy-L-proline from Example 49(a) istreated with hydrochloric acid according to the procedure of Example3(a) to yield 3,4-dehydro-4-ethenyl-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-ethenyl-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-ethenyl-L-proline from part (a) is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-ethenyl-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-4-ethenyl-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-4-ethenyl-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 51 4-Allyl-4-Hydroxy-1-(3-mercapto-1-oxopropyl)-L-proline (a)N-Carbobenzyloxy-4-allyl-4-hydroxy-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of allylmagnesium bromide for the phenylmagnesium bromide oneobtains N-carbobenzyloxy-4-allyl-4-hydroxy-L-proline.

(b) 1-[3-(Acetylthio)-1-oxopropyl]-4-allyl-4-hydroxy-L-proline

The N-carbobenzyloxy-4-allyl-4-hydroxy-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-allyl-4-hydroxy-L-proline. This amino acid is reacted with3-acetylthiopropionyl chloride according to the procedure of Example1(c) to yield1-[3-(acetylthio)-1-oxopropyl]-4-allyl-4-hydroxy-L-proline.

(c) 4-Allyl-4-hydroxy-1-(3-mercapto-1-oxopropyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield4-allyl-4-hydroxy-1-(3-mercapto-1-oxopropyl)-L-proline.

EXAMPLE 52(2S)-4-Allyl-2,5-dihydro-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-allyl-L-proline

The N-carbobenzyloxy-4-allyl-4-hydroxy L-proline from Example 51(a) istreated with hydrochloric acid according to the procedure of Example3(a) to yield 3,4-dehydro-4-allyl-L-proline.

(b)(2S)-1-[3-(Acetylthio)-1-oxopropyl]-4-allyl-2,5-dihydro-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-allyl-L-proline from part (a) is reacted with3-acetylthiopropionyl chloride according to the procedure of Example3(b) to yield(2S)-1-[3-(acetylthio)-1-oxopropyl]-4-allyl-2,5-dihydro-1H-pyrrole-2-carboxylicacid.

(c)(2S)-4-Allyl-2,5-dihydro-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield(2S)-4-allyl-2,5-dihydro-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 53[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-propargyl-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-propargyl-L-proline

Following the procedure of Example 5(a) but substituting an equivalentamount of propargyl lithium for the phenyl lithium one obtainsN-carbobenzyloxy-4-hydroxy-4-propargyl-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-propargyl-L-proline

The N-carbobenzyloxy-4-hydroxy-4-propargyl-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-propargyl-L-proline. This amino acid is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-propargyl-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-propargyl-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-propargyl-L-proline.

EXAMPLE 54[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-propargyl-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-propargyl-L-proline

The N-carbobenzyloxy-4-hydroxy-4-propargyl-L-proline from Example 53(a)is treated with hydrochloric acid according to the procedure of Example3(a) to yield 3,4-dehydro-4-propargyl-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-propargyl-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-propargyl-L-proline from part (a) is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-propargyl-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-propargyl-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-propargyl-1H-pyrrole-2-carboxylicacid.

EXAMPLE 55[1(S)]-4-Ethynyl-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline(a) N-Carbobenzyloxy-4-ethynyl-4-hydroxy-L-proline

Following the procedure of Example 5(a) but substituting an equivalentamount of ethynyl lithium for the phenyl lithium one obtainsN-carbobenzyloxy-4-ethynyl-4-hydroxy-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-ethynyl-4-hydroxy-L-proline

The N-carbobenzyloxy-4-ethynyl-4-hydroxy-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-ethynyl-4-hydroxy-L-proline. This amino acid is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-ethynyl-4-hydroxy-L-proline.

(c)[1(S)]-4-Ethynyl-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-ethynyl-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline.

EXAMPLE 56[1(S),2S]-2,5-Dihydro-4-ethynyl-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-ethynyl-L-proline

The N-carbobenzyloxy-4-ethynyl-4-hydroxy-L-proline from Example 55(a) istreated with hydrochloric acid according to the procedure of Example3(a) to yield 3,4-dehydro-4-ethynyl-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-ethynyl-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-ethynyl-L-proline from part (a) is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-ethynyl-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-4-ethynyl-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-4-ethynyl-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 57[1(S)]-4-Cyclohexyl-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline(a) N-Carbobenzyloxy-4-cyclohexyl-4-hydroxy-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of cyclohexylmagnesium chloride for the phenylmagnesium bromideone obtains N-carbobenzyloxy-4-cyclohexyl-4-hydroxy-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-cyclohexyl-4-hydroxy-L-proline

The N-carbobenzyloxy-4-cyclohexyl-4-hydroxy-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-cyclohexyl-4-hydroxy-L-proline. This amino acid is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-cyclohexyl-4-hydroxy-L-proline.

(c)[1(S)]-4-Cyclohexyl-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline

The product from part (b) is reacted with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-cyclohexyl-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline.

EXAMPLE 58[1(S),2S]-4-Cyclohexyl-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid (a) 4-Cyclohexyl-3,4-dehydro-L-proline

The N-carbobenzyloxy-4-cyclohexyl-4-hydroxy-L-proline from Example 57(a)is treated with hydrochloric acid according to the procedure of Example3(a) to yield 4-cyclohexyl-3,4-dehydro-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-cyclohexyl-2,5-dihydro-1H-pyrrole-2-carboxylicacid

The 4-cyclohexyl-3,4-dehydro-L-proline from part (a) is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-cyclohexyl-2,5-dihydro-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-4-Cyclohexyl-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-4-cyclohexyl-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 594-Hydroxy-1-(3-mercapto-1-oxopropyl)-4-(phenylpropyl)-L-proline (a)N-Carbobenzyloxy-4-hydroxy-4-(phenylpropyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of (phenylpropyl) magnesium bromide for the phenylmagnesiumbromide one obtainsN-carbobenzyloxy-4-hydroxy-4-(phenylpropyl)-L-proline.

(b) 1-[3-(Acetylthio)-1-oxopropyl]-4-hydroxy-4-(phenylpropyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(phenylpropyl)-L-proline from part (a)is hydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-(phenylpropyl)-L-proline. This amino acid is reacted with3-acetylthiopropionyl chloride according to the procedure of Example1(c) to yield1-[3-(acetylthio)-1-oxopropyl]-4-hydroxy-4-(phenylpropyl)-L-proline.

(c) 4-Hydroxy-1-(3-mercapto-1-oxopropyl)-4-(phenylpropyl)-L-proline

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 2 to yield4-hydroxy-1-(3-mercapto-1-oxopropyl)-4-(phenylpropyl)-L-proline.

EXAMPLE 60[2S]-2,5-Dihydro-1-(3-mercapto-1-oxopropyl)-4-(phenylpropyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(phenylpropyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(phenylpropyl)-L-proline from Example59(a) is treated with hydrochloric acid according to the procedure ofExample 3(a) to yield 3,4-dehydro-4-(phenylpropyl)-L-proline.

(b)[2S]-1-[3-(Acetylthio)-1-oxopropyl]-2,5-dihydro-4-(phenylpropyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(phenylpropyl)-L-proline from part (a) is reacted with3-acetylthiopropionyl chloride according to the procedure of Example3(b) to yield[2S]-1-[3-(acetylthio)-1-oxopropyl]-2,5-dihydro-4-(phenylpropyl)-1H-pyrrole-2-carboxylicacid.

(c)[2S]-2,5-Dihydro-1-(3-mercapto-1-oxopropyl)-4-(phenylpropyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[2S]-2,5-dihydro-1-(3-mercapto-1-oxopropyl)-4-(phenylpropyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 61[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(α-naphthyl)-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-(α-naphthyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of α-naphthylmagnesium bromide for the phenylmagnesium bromideone obtains N-carbobenzyloxy-4-hydroxy-4-(α-naphthyl)-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(α-naphthyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(α-naphthyl)-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-(α-naphthyl)-L-proline. This amino acid is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(α-naphthyl)-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(α-naphthyl)-L-proline

The product from part (b) is reacted with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(α-mercapto)-L-proline.

EXAMPLE 62[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(α-naphthyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(α-naphthyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(α-naphthyl)-L-proline from Example61(a) is treated with hydrochloric acid according to the procedure ofExample 3(a) to yield 3,4-dehydro-4-(α-naphthyl)-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(α-naphthyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(α-naphthyl)-L-proline from part (a) is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(α-naphthyl)-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(α-naphthyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(α-naphthyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLE 63[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(β-naphthyl)-L-proline(a) N-Carbobenzyloxy-4-hydroxy-4-(β-naphthyl)-L-proline

Following the procedure of Example 1(a) but substituting an equivalentamount of β-naphthyl magnesium bromide for the phenylmagnesium bromideone obtains N-carbobenzyloxy-4-hydroxy-4-(β-naphthyl)-L-proline.

(b)[1(S)]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(β-naphthyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(β-naphthyl)-L-proline from part (a) ishydrogenated according to the procedure of Example 1(b) to yield4-hydroxy-4-(β-naphthyl)-L-proline. This amino acid is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 1(c) to yield[1(S)]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-(β-naphthyl)-L-proline.

(c)[1(S)]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(β-naphthyl)-L-proline

The product from part (b) is reacted with concentrated ammonia accordingto the procedure of Example 2 to yield[1(S)]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(β-naphthyl)-L-proline.

EXAMPLE 64[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(β-naphthyl)-1H-pyrrole-2-carboxylicacid (a) 3,4-Dehydro-4-(β-naphthyl)-L-proline

The N-carbobenzyloxy-4-hydroxy-4-(β-naphthyl)-L-proline from Example63(a) is treated with hydrochloric acid according to the procedure ofExample 3(a) to yield 3,4-dehydro-4-(β-naphthyl)-L-proline.

(b)[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(β-naphthyl)-1H-pyrrole-2-carboxylicacid

The 3,4-dehydro-4-(β-naphthyl)-L-proline from part (a) is reacted withD-3-acetylthio-2-methylpropionyl chloride according to the procedure ofExample 3(b) to yield[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-(β-naphthyl)-1H-pyrrole-2-carboxylicacid.

(c)[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(β-naphthyl)-1H-pyrrole-2-carboxylicacid

The product from part (b) is treated with concentrated ammonia accordingto the procedure of Example 4 to yield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-(β-naphthyl)-1H-pyrrole-2-carboxylicacid.

EXAMPLES 65-72

Following the procedure of Example 1(b) but substituting for theD-3-acetylthio-2-methylpropionyl chloride the acid chloride listed belowin Col. I one obtains the acylmercapto product listed below in Col. II.

    ______________________________________                                        Column I      Column II                                                       ______________________________________                                        D-3-benzoylthio-2-                                                                          [1(S),4R]-1-[3-(benzoylthio)-2-                                 methylpropionyl                                                                             methyl-1-oxopropyl]-4-hydroxy-4-                                chloride      phenyl-L-proline                                                D-3-[[(2-thienyl)car-                                                                       [1(S),4R]-1-[3-[[(2-thienyl)carbony]-                           bonyl]-thio]-2-methyl-                                                                      thio]-2-methyl-1-oxopropyl]-4-hydroxy-                          propionyl chloride                                                                          4-phenyl-L-proline                                              D-3-[[(2,2,2-trichloro-                                                                     [1(S),4R]-1-[3-[[(2,2,2-trichloroethyl)-                        ethyl)-carbonyl]thio]-2-                                                                    carbonyl]thio]-2-methyl-1-oxopropyl]-                           methylpropionyl                                                                             4-hydroxy-4-phenyl-L-proline                                    chloride                                                                      D-3-[[(2-furyl)carbonyl]-                                                                   [1(S),4R]-1-[3-[[(2-furyl)carbonyl]-                            thio]-2-methylpropionyl                                                                     thio]-2-methyl-1-oxopropyl]-4-hydroxy-                          chloride      4-phenyl-L-proline                                              D-3-[[(4-pyridyl)car-                                                                       [1(S),4R]-1-[3-[[(4-pyridyl)carbonyl]-                          bonyl]-thio]-2-methyl-                                                                      thio]-2-methyl-1-oxopropyl]-4-hydroxy-                          propionyl chloride                                                                          4-phenyl-L-proline                                              D-3-[[(4-methylphenyl)                                                                      [1(S),4R]-1-[3-[[(4-methylphenyl)car-                           carbonyl]thio]-2-methyl-                                                                    bonyl]thio]-2-methyl-1-oxopropyl]-4-                            propionyl chloride                                                                          hydroxy-4-phenyl-L-proline                                      2-[[(phenylmethyl)car-                                                                      (4R)-1-[2-[[(phenylmethyl)car-                                  bonyl]-thio]acetyl                                                                          bonyl]thio]-1-oxoethyl]-4-hydroxy-                              chloride      4-phenyl-L-proline                                              3-benzoylthiopropionyl                                                                      (4R)-1-[3-(benzoylthio)-1-oxopropyl]-                           chloride      4-hydroxy-4-phenyl-L-proline                                    ______________________________________                                    

EXAMPLES 73-79

Following the procedure of Example 3(b) but substituting for theD-3-acetylthio-2-methylpropionyl chloride the acid chloride listed belowin Col. I one obtains the acylmercapto product listed below in Col. II.

    ______________________________________                                        Col. I        Col. II                                                         ______________________________________                                        D-3-benzoylthio-2-                                                                          [1(S),2S]-1-[3-(benzoylthio)-2-                                 methylpropionyl                                                                             methyl-1-oxopropyl]-2,5-dihydro-4-                              chloride      phenyl-1H--pyrrole-2-carboxylic acid                            3-benzoylthiopropionyl                                                                      (2S)-1-[3-(benzoylthio)-1-oxopropyl]-                           chloride      2,5-dihydro-4-phenyl-1H--pyrrole-2-                                           carboxylic acid                                                 D-3-[[(2,2,2-trichloro-                                                                     [1(S),2S]-1-[3-[[(2,2,2-trichloroethyl)-                        ethyl)-carbonyl]thio]-2-                                                                    carbonyl]thio]-2-methyl-1-oxopropyl]-                           methylpropionyl                                                                             2,5-dihydro-4-phenyl-1H--pyrrole-2-                             chloride      carboxylic acid                                                 2-[[(2-thienyl)car-                                                                         (2S)-1-[2-[[(2-thienyl)carbonyl]thio]-                          bonyl]-thio]acetyl                                                                          1-oxoethyl]-2,5-dihydro-4-phenyl-1H--                           chloride      pyrrole-2-carboxylic acid                                       D-3-[[(2-furyl)carbonyl]-                                                                   [1(S),2S]-1-[3-[[(2-furyl)carbonyl]thio]-                       thio]-2-methylpropionyl                                                                     2-methyl-1-oxopropyl]-2,5-dihydro-4-                            chloride      phenyl-1H--pyrrole-2-carboxylic acid                            D-3-[[(3-pyridyl)car-                                                                       [1(S),2S]-1-[3-[[(3-pyridyl)car-                                bonyl]-thio]-2-methyl                                                                       bonyl]thio]-2-methyl-1-oxopropyl]-                              propionyl chloride                                                                          2,5-dihydro-4-phenyl-1H--pyrrole-2-                                           carboxylic acid                                                 D-3-[[[(4-methoxyphenyl)                                                                    [1(S),2S]-1-[3-[[[(4-methoxyphenyl)-                            methyl]-carbonyl]thio]-2-                                                                   methyl]carbonyl]thio]-2-methyl-1-                               methyl propionyl                                                                            oxopropyl]2,5-dihydro-4-phenyl-1H--                             chloride      pyrrole-2-carboxylic acid                                       ______________________________________                                    

EXAMPLE 80[1(S),1'(S),4R,4'R]-1,1'-[Dithiobis(2-methyl-1-oxopropane-3,1-diyl)]bis[4-hydroxy-4-phenyl-L-proline]

A solution of the product from Example 2 is dissolved in ethanol,stirred and treated with a solution of one equivalent of iodine inethanol. The pH of the solution is maintained at 6-7 by the addition ofN-sodium hydroxide solution. The solvent is evaporated and the residueextracted with ethyl acetate. After drying over MgSO₄, the solution isfiltered and the solvent evaporated to give[1(S),1'(S),4R,4'R]-1,1'-[dithiobis(2-methyl-1-oxopropane-3,1-diyl)]bis[4-hydroxy-4-phenyl-L-proline].

EXAMPLE 81[1(S),1'(S),2S,2'S]-1,1'-[Dithiobis(2-methyl-1-oxopropane-3,1-diyl)]bis[4-phenyl-1H-pyrrole-2-carboxylicacid]

A solution of the product from Example 4 is dissolved in ethanol,stirred and treated with a solution of one equivalent of iodine inethanol. The pH of the solution is maintained at 6-7 by the addition ofN-sodium hydroxide solution. The solvent is evaporated and the residueextracted with ethyl acetate. After drying over MgSO₄, the solution isfiltered and the solvent evaporated to give[1(S),1'(S),2S,2'S]-1,1'-[dithiobis(2-methyl-1-oxopropane-3,1-diyl)]bis[4-phenyl-1H-pyrrole-2-carboxylicacid].

EXAMPLE 82[1(S),4R]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline,methyl ester

A solution of the product from Example 1 in ether is treated with aslight excess of diazomethane. After standing at room temperature, thesolvent is evaporated to give[1(S),4R]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-proline,methyl ester.

EXAMPLE 83[1(S),2S]-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid, methyl ester

A solution of the product from Example 3 in ether is treated with aslight excess of diazomethane. After standing at room temperature, thesolvent is evaporated to give[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid, methyl ester.

EXAMPLE 84[1(S),4R]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-proline,methyl ester

The methyl ester product from Example 82 is treated with concentratedammonia according to the procedure of Example 2 to give[1(S),4R]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-proline,methyl ester.

EXAMPLE 85[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid, methyl ester

The methyl ester product from Example 83 is treated with concentratedammonia according to the procedure of Example 4 to give[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid, methyl ester.

EXAMPLE 86[1(S),4R]-4-Hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-proline,sodium salt

An aqueous solution of the product from Example 2 is treated with aslight excess of sodium bicarbonate. The solution is lyophilized toyield[1(S),4R]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-proline,sodium salt.

EXAMPLE 87[1(S),2S]-2,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid, sodium salt

An aqueous solution of the product from Example 4 is treated with aslight excess of sodium bicarbonate. The solution is lyophilized toyield[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid, sodium salt.

EXAMPLE 88

1000 tablets each containing the following ingredients:

    ______________________________________                                        [1(S),2S]-2,5-Dihydro-1-                                                                             100    mg.                                             (3-mercapto-2-methyl-1-                                                       oxopropyl)-4-phenyl-1H--                                                      pyrrole-2-carboxylic acid                                                     Corn starch            50     mg.                                             Gelatin                7.5    mg.                                             Avicel (microcrystalline                                                                             25     mg.                                             cellulose)                                                                    Magnesium stearate     2.5    mg.                                                                    185    mg.                                             ______________________________________                                    

are prepared (from sufficient bulk quantities) by mixing the[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid and corn starch with an aqueous solution of the gelatin. Themixture is dried and ground to a fine powder. The Avicel and then themagnesium stearate are admixed with granulation. This mixture is thencompressed in a tablet press to form 1000 tablets each containing 100mg. of active ingredient.

EXAMPLE 89

Tablets each containing 100 mg. of[1(S),4R]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-prolineare produced as described in Example 88.

EXAMPLE 90

1000 tablets each containing the following ingredients:

    ______________________________________                                        [1(S),2S]-1-[3-(Acetylthio)-                                                                          50     mg.                                            2-methyl-1-oxopropyl]-2,5-                                                    dihydro-4-phenyl-1H--pyrrole-                                                 2-carboxylic acid                                                             Lactose                 25     mg.                                            Avicel                  38     mg.                                            Cornstarch              15     mg.                                            Magnesium stearate      2      mg.                                                                    130    mg.                                            ______________________________________                                    

are prepared by admixing the[1(S),2S]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-2,5-dihydro-4-phenyl-1H-pyrrole-2-carboxylicacid, lactose and Avicel and then blending with the corn starch.Magnesium stearate is added. The dry mixture is compressed in a tabletpress to form 1000 130 mg. tablets each containing 50 mg. of activeingredient. The tablets are coated with a solution of Methocel E 15(methyl cellulose) including as a color a lake containing yellow #6.

EXAMPLE 91

Tablets each containing 50 mg. of[1(S),4R]-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4-hydroxy-4-phenyl-L-prolineare produced as described in Example 90.

EXAMPLE 92

Two piece #1 gelatin capsules each containing 100 mg. of[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid, sodium salt, are filled with a mixture of the followingingredients:

    ______________________________________                                        [1(S),2S]-2,5-Dihydro-1-                                                                              100    mg.                                            (3-mercapto-2-methyl-1-oxo-                                                   propyl)-4-phenyl-1H--pyrrole-                                                 2-carboxylic acid, sodium salt                                                Magnesium stearate      7      mg.                                            Lactose                 193    mg.                                            ______________________________________                                    

EXAMPLE 93

Gelatin capsules containing 100 mg. of[1(S),4R]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-prolineare produced as described in Example 92.

EXAMPLE 94

An injectable solution is produced as follows:

    ______________________________________                                        [1(S),2S]-2,5-Dihydro-1-                                                                              500    g.                                             (3-mercapto-2-methyl-1-                                                       oxopropyl)-4-phenyl-1H--                                                      pyrrole-2-carboxylic acid                                                     Methyl paraben          5      g.                                             Propyl paraben          1      g.                                             Sodium chloride         25     g.                                             Water for injection qs. 5      l                                              ______________________________________                                    

The active substance, preservatives and sodium chloride are dissolved in3 liters of water for injection and then the volume is brought up to 5liters. The solution is filtered through a sterile filter andaseptically filled into presterilized vials which are then closed withpresterilized rubber closures. Each vial contains 5 ml. of solution in aconcentration of 100 mg. of active ingredient per ml. of solution forinjection.

EXAMPLE 95

An injectable solution containing[1(S),4R]-4-hydroxy-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-prolineis prepared as described in Example 94.

EXAMPLE 95

6000 tablets each containing the following ingredients:

    ______________________________________                                        [1(S),2S]-2,5-Dihydro-1-                                                                             100    mg.                                             (3-mercapto-2-methyl-1-                                                       oxopropyl)-4-phenyl-1H--                                                      pyrrole-2-carboxylic acid                                                     Avicel (microcrystalline                                                                             100    mg.                                             cellulose)                                                                    Hydrochlorothiazide    12.5   mg.                                             Lactose U.S.P.         113    mg.                                             Corn starch U.S.P.     17.5   mg.                                             Stearic acid U.S.P.    7      mg.                                                                    350    mg.                                             ______________________________________                                    

are produced from sufficient bulk quantities by slugging the[1(S),2S]-2,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-1H-pyrrole-2-carboxylicacid, Avicel and a portion of the stearic acid. The slugs are ground andpassed through a #2 screen, then mixed with the hydrochlorothiazide,lactose, corn starch and remainder of the stearic acid. The mixture iscompressed into 350 mg. capsule shaped tablets in a tablet press. Thetablets are scored for dividing in half.

EXAMPLE 96

Tablets containing[1(S),4R]-4-hydroxy-(3-mercapto-2-methyl-1-oxopropyl)-4-phenyl-L-prolineand hydrochlorothiazide can be prepared as described in Example 95.

The products of Examples 5 to 87 can also be formulated according toprocedures of Examples 88 to 96.

What is claimed is:
 1. A compound of the formula ##STR24## wherein R ishydrogen or lower alkyl;R₁ is lower alkyl, lower alkenyl, lower alkynyl,##STR25## --(CH₂)_(m) -cycloalkyl wherein said cycloalkyl ring is of 3to 7 carbons, α-naphthyl, β-naphthyl, ##STR26## wherein said --(CH₂)_(m)-bridge is attached to an available carbon atom, or ##STR27## whereinsaid --(CH₂)_(m) -bridge is attached to an available carbon atom; R₆ ishydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons,lower alkylthio of 1 to 4 carbons, chloro, fluoro, bromo,trifluoromethyl or hydroxy; m is zero, one, two or three; and X is O orS.
 2. A compound of claim 1 wherein R is hydrogen.
 3. The compound ofclaim 2 wherein R₁ is phenyl.